APPLICANT'S ABSTRACT: There is a growing consensus that alcoholism (alcohol abuse and dependence) develops over time through a complex interaction between a maturing person and the environment, where expression of risk is dependent upon individual experience as well as diathesis. Environmental settings will trigger or suppress risk over the life span. However, developmental changes are difficult to demonstrate without clear knowledge of initial vulnerability markers and environmental risk enhancers that are specific to alcoholism. The complexity of etiology and the inconsistent results from genetic studies have discouraged interest in research on single-gene effects in alcoholism. However, definitive research with homogeneous subtypes and truly relevant candidate genes has not been conducted. Biological markers have been identified for the Antisocial Alcoholism subtype, specifically lower serotonin (5-HT) function. The consistency of this research provides a strong rationale for testing associations with candidate genes that relate to 5-HT metabolism. Single gene effects may be detectable with homogeneous subtypes. The proposed study uses a family-based design, the haplotype relative risk method (a study design that prevents confounding by ethnic differences between control and affected groups). This proposal requests sufficient funding for a definitive study of autosomal serotonin markers (tryptophan hydroxylase, the serotonin transporter, and three serotonin receptor types [lA, lB, 2A]) in male antisocial alcoholics (n=50 probands and their 100 parents), and funds for conducting two feasibility studies: (l) X-linked markers (monamine oxidase A and B and one serotonin receptor type [2C]) in 10 male probands and their 20 parents; and (2) autosomal and X-linked markers in 10 women and their 20 parents. For this exploratory/developmental study, a sample with homogeneous ethnic background will be sought. The specific aims are to test genetic associations between antisocial alcoholism and polymorphisms in tryptophan hydroxylase, the serotonin transporter, monamine oxidase A and B, and four serotonin receptor types (lA, lB, 2A, and 2C). The research plan will also allow preservation of DNA for future use and assessment of the feasibility of future studies involving sib-pair linkage, recruitment of adequate samples of other races, and longitudinal studies of genetic and environmental effects on chronicity of the disorder.